Delivery of RNAi Therapeutics to the Airways—From Bench to Bedside

Qiu, Yingshan; Lam, Jenny K. W.; Leung, Susan W. S.; Liang, Wanling

Many transcription factors including nuclear factor-κB (NF-κB) [168] , signal transducer and activator of transcription factor 6 (STAT6) [166] and GATA-binding protein 3 (GATA3) [170] are involved in the production T h 2 cytokine in the airways of patients with asthma. They were investigated as targets for RNAi in the management of asthmatic inflammation. NF-κB plays a key role in the expression of many pro-inflammatory proteins [191] . Inhibition of NF-κB pathway in the lungs was reported to be beneficial in asthma model [176, 192] . One approach to inhibit the activation of NF-κB signaling pathway is to target receptor-interacting protein 2 (Rip2), which is a transcriptional product and an activator of NF-κB. Suppression of Rip2 expression was achieved in mice by intratracheal delivery of siRNA, resulting in the inhibition of ovalbumin (OVA)-induced cytokine release, inflammatory cell infiltration, mucus hypersecretion and serum IgE level. This result suggested that Rip2 could be a novel therapeutic target for the treatment of asthma [168] . Consistent with this finding, suppression of STAT6 [10] and GATA3 [170, 193] in murine model of allergen-induced asthma by RNAi significantly inhibited the expression of downstream T h 2 cytokines. These studies support the hypothesis of using RNAi molecules targeting transcription factors to manage airway inflammation and AHR of asthma.